This application is a 371 of PCT/CH/99/00337, filed Jul. 22, 1999.
The present invention relates to a pressure-liquefied propellant mixture based on hydrofluoro-alkanes, the use of this propellant mixture in aerosol formulations, and a process for the preparation of the aerosol formulations.
Many gases, such as carbon dioxide and nitrogen, can indeed be liquefied under pressure, but are not suitable as propellants for metered-dose aerosols, because the internal pressure in the container decreases very greatly as it becomes more empty. For this reason, only those propellants are used for medicinal metered-dose aerosols, which propellants can be liquefied at room temperature and in any case only lead to a slight decrease in the internal pressure in the container when the contents are successively removed by spraying. These include the short-chain alkanes, such as propane, butane and isobutane, and the chlorofluorocarbons (CFCs), such as trichlorofluoromethane (F11), dichlorodifluoromethane (F12) and 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114).
WO-A-93/17665 in fact discloses a method for the administration of physiologically active compounds, in which a supercritical liquid solution is formed from a supercritical liquid solvent and the active compound and this is then converted into the subcritical range. The supercritical solvent used was carbon dioxide, it being stated that, in addition to carbon dioxide, dinitrogen oxide, chlorofluorocarbons such as dichlorodifluoromethane and trichlorofluoromethane, xenon, sulfur hexafluoride, ethanol, acetone, propane, water and mixtures thereof are suitable.
In Research Disclosure (1978), 170, 58, XP-002090730, it was further mentioned that some fluorocarbon and chlorofluorocarbon propellants can be used in aerosol products such as hairsprays, deodorants and antiperspirants as co-propellants together with carbon dioxide or dinitrogen monoxide. The 2,2-dichloro-1,1,1-trifluoroethane (F123), 1,2-dichloro-1,1-difluoroethane (F132b), 2-chloro-1,1,1-trifluoroethane (F133a), 1,1-dichloro-1-fluoroethane (F114b) and 1-chloro-1,1-difluoroethane (F142b) mentioned as examples are chlorinated and, moreover, not very customary propellants. A hairspray in which trifluoromonochloroethane (F133a) together with carbon dioxide and/or dinitrogen monoxide is used as a propellant mixture is also disclosed in U.S. Pat. No. 4,397,836.
On account of the ozone problem caused by the elimination of free-radical chlorine atoms from CFCs, in the Montreal Agreement many countries came to an understanding that they would no longer use CFCs as propellants in future. Suitable CFC substitutes for the medicinal field are fluorinated alkanes (in the context of the present invention also designated as HFA), especially 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), as these are inert and have a very low toxicity. On account of their physical properties, such as pressure, density, etc., they are particularly suitable for replacing CFCs such as F11, F12 and F114 as propellants in metered-dose aerosols.
U.S. Pat. No. 4 139 607, on the other hand, proposed a propellant system formed from liquefied bis(difluoromethyl) ether and gaseous carbon dioxide, which in contrast to combinations of carbon dioxide with other known propellants such as trichloro-fluoromethane or methylene chloride should afford satisfactory aerosol samples, but, however, has not been accomplished. The document in fact mentions that other propellants such as dinitrogen monoxide, hydrocarbons and fluorohydrocarbons or liquid carriers, such as ethanol, perchloroethylene, trichloroethylene, acetone, amyl acetate, water and the like, can be added to the propellant system; the disclosed formulations, however, mostly contain about 50% of ethanol. In Derwent Abstract AN 89-184245, it is only stated that in aerosol pressure packs for the administration of medicaments instead of CFCs, hydrocarbons, such as butane and pentane, other compressed gases, such as carbon dioxide, dimethyl ether, nitrogen and dinitrogen oxide, or fluorohydrocarbons could also be used.
Medicinal aerosol preparations containing hydrofluoroalkanes such as HFA 134a are already embraced by the teaching of U.S. Pat. No. 2,868,691 and U.S. Pat. No. 3,014,844 and disclosed in DE-A-2 736 500 and EP-A-0 372 777. Examples of formulations containing HFA 227 are found, for example, in WO-A-91/11495, EP-A-0 504 112 and EP-B-0 550 031. It is known from various publications that the customary excipients used in CFC-containing metered-dose aerosols, such as lecithin, sorbitan trioleate and oleic acid, only dissolve inadequately in hydrofluoroalkanes such as HFA 134a and HFA 227, because a chain extension and the substitution of the chlorine atoms by fluorine atoms leads to a worsening of the solubility properties of the permitted excipients mentioned. Even in the case of CFCs, which are considerably better solvents than HFAs, ethanol or other cosolvents were often added to improve the solubility in order to be able to administer pharmaceutical substances such as isoprenaline and epinephrine (cf. U.S. Pat. No. 2,868,691) as an aerosol. It was therefore obvious to improve not only the solubility of CFCs, but also that of HFAs, by addition of ethanol. Examples of this are found in the technical literature and in various patent applications. Alternatively to this, there are a number of developments of pressure-liquefied aerosol preparations containing HFA 134a and/or HFA 227 which use propellant-soluble excipients, such as fluorinated surface-active substances (WO-A-91/04011), mono- or diacetylated glycerides (EP-A-0 504 112) or polyethoxylated compounds (WO-A-92/00061), which can be dissolved in the necessary amount in the two propellants even without addition of ethanol.
For CFC-free medicinal aerosol preparations having a high vapor pressure, the propellant preferably used today is usually HFA 134a (vapor pressure about 6 bar at 20xc2x0 C.) and for those with a lower vapor pressure it is HFA 227 (vapor pressure about 4.2 bar at 20xc2x0 C.). Both propellants differ with respect to their density (about 1.4 mg/ml for HFA 227 and about 1.2 mg/ml for HFA 134a at 20xc2x0 C.), which is particularly of importance for suspensions. If the active compound has a higher density than the propellant, sedimentation occurs; if its density is lower, flotation occurs. To solve the problem, it is therefore suggested under certain circumstances to use propellant mixtures and/or, to lower the density, to add cosolvents such as ethanol, diethyl ether or other low-boiling solvents or propellants such as n-butane. A significant disadvantage of the hydrofluoroalkanes is their relatively low dissolving power in comparison with CFCs, in particular in comparison with F11. The solvent properties decrease with increasing chain length in the sequence F11 greater than HFA 134a  greater than HFA 227. For this reason, the suspending aids customarily used in CFCs, such as sorbitan trioleate, lecithin and oleic acid, can no longer be dissolved in the customary concentrations (weight ratios of typically approximately 1:2 to 1:20, based on the active compound) by addition of polar solvents without increasing the hydrophilicity.
It is generally known that in the case of suspension formulations only active compound particles which are smaller than 6 xcexcm are respirable. For the desired deposition thereof in the lungs, these must therefore be comminuted or micronized before processing by means of special procedures, such as using pinned-disk, ball or air-jet mills. A grinding process as a rule leads to an increase in surface area, which is accompanied by an increase in the electrostatic charge of the micronized active compound, on account of which the flow behaviour and the active compound dispersion is usually impaired. As a result of the interfacial and charge activities, there is often an agglomeration of active compound particles or alternatively adsorption of active compound at interfaces, which becomes conspicuous, for example, in the accumulation on equipment or container surfaces.
In aerosol preparations in which the active compound is present suspended in liquefied propellant, adsorption or ring formation in the container can occur at the place where the liquid phase changes into the gas phase. Without wetting the micronized active compound particles or conducting away charges and modifying their surface properties, problems can occur during dispersion or suspension, in the hydrofluoroalkanes mentioned. The lack of wetting or dispersion of the active compound particles also results in these in many cases having a high adsorption tendency and adhering to surfaces, such as the container inner wall or the valve, which then leads to an underdosage and to a poor dosage accuracy from puff of spray to puff of spray. In the case of suspensions, it is therefore necessary as a rule to add a surface-active substance or a glidant in order to lower the adsorption at interfaces, to stabilize the suspensions and to ensure the dosage accuracy. A change or reduction in the proportion of the inhalable, respirable particles, the so-called fine particle fraction (FPF) or fine particle dose (FPD), occurring in the course of storage, which leads to a decrease in the activity of the HFA preparation, is particularly problematical.
To overcome the problems presented above, as a rule surface-active substances are therefore added, as were already used earlier in the CFC-containing formulations. Alternatively to this, in certain cases a modification of the surface properties by means of various measures (e.g. coating) may help to minimize these undesired effects. Because, however, surface-active agents such as oleic acid, sorbitan trioleate and lecithin only dissolve inadequately in hydrofluoroalkanes such as HFA 134a and HFA 227, in many cases ethanol is or must be added as a cosolvent so that the pharmaceutical technology problems can be controlled better.
If, however, ethanol is added in a higher concentration, the density of the propellant mixture is reduced, which can lead to an undesired sedimentation of active compound, especially in the case of suspensions. Moreover, a xe2x80x9cwet sprayxe2x80x9d can undesirably be obtained, because the propellant evaporates much more rapidly than ethanol. In addition, however, as a result of the increase in solubility during storage, the active compounds can also start to dissolve, which then leads to crystal growth and thus, in turn, to a reduction in the amount of inhalable, respirable particles, the so-called fine particle dose (FPD).
To measure the aerodynamic particle size distribution or the proportion of the dose which can be deposited in the lungs, the so-called fine particle dose (FPD), of inhalable, respirable particles in an aerosol, impactors, such as the 5-stage multistage liquid impinger (MSLI) or the 8-stage Andersen cascade impactor (ACI), which are described in Chapter  less than 601 greater than  of the United States Pharmacopeia (USP) or in the Inhalants Monograph of the European Pharmacopeia (Ph. Eur.) are suitable. Using these apparatuses, the aerodynamic deposition behaviour of the aerosol cloud can be investigated in the laboratory (in vitro) . By means of a xe2x80x9clog-probability plotxe2x80x9d (logarithmic representation of the probability distribution), the mean aerodynamic particle diameter (Mass Median Aerodynamic Diameter (MMAD)) of aerosol preparations can then be calculated. From this, it can be deduced whether the active compound is more likely to be deposited in the upper or lower area of the lungs.
If the active compound is present in the HFA propellant/ethanol mixture not in suspended form, but in dissolved form, problems with respect to the standard deviation of the dosage accuracy per stroke are usually less pronounced. If, however, a larger amount of ethanol is used for this, on rinsing empty the container a xe2x80x9chead spacexe2x80x9d effect occurs as follows: the proportion of ethanol, which has a lower vapor pressure and a lower density, increases and that of propellant having higher density and higher vapor pressure decreases. On spraying or as the container becomes more empty, the concentration ratio of propellant to ethanol changes, which on account of the density difference leads to a reduction in the mass of a puff of spray and thus also in the content of a puff of spray or active compound. It is additionally disadvantageous that at higher ethanol concentrations of, for example, 10%-30%, the content of inhalable particles ( less than 6 xcexcm) usually decreases, because the spray affords droplets having a greater aerodynamic diameter on account of the different evaporation properties of ethanol in comparison to the propellant. As a result of this, there is a reduction in the fine particle dose (FPD) which is crucial for the activity.
In a solution aerosol with the same ethanol content, a higher fine particle fraction (FPF), i.e. a greater percentage of inhalable droplets, is customarily obtained with HFA 134a in comparison to HFA 227, which is to be attributed to the higher pressure of HFA 134a. In principle, it is true that the higher the internal pressure in the aerosol container, the finer the particle spectrum of the aerosol cloud. Solution aerosols having a low ethanol content therefore as a rule have a smaller MMAD (0.8-1.5 xcexcm) than suspension aerosols (2-4 xcexcm), when using fine atomizing nozzles. This is connected with the fact that droplets are generated as an aerosol cloud in the case of solution aerosols and particles in the case of suspension aerosols.
For the topical application of active compounds in the area of the bronchi and bronchioles, particle sizes of about 2-4 xcexcm are advantageous, as are customarily achieved with suspension formulations. Smaller particles which pass into the alveolar area are partly exhaled ( less than 0.5 xcexcm) or pass into the systemic circulation by absorption. It follows from this that aerosol preparations for systemic application should favourably have particle sizes of about 0.5 xcexcm-2 xcexcm, where, for example, a monodisperse aerosol having a very high proportion of particles in the range of about 1 xcexcm would be particularly advantageous. Depending on the desired site of deposition, a smaller or larger MMAD and, if appropriate, a monodisperse distribution spectrum are therefore preferred. The following holds with respect to the aerodynamics: the greater the mass of the particles the greater their tendency to fly on in a straight line. It results from this that if there is a change in the direction of flow, impaction of particles occurs. It is known from deposition studies that even in the case of an optimum inhalation maneuver only about 20% of the particles emitted from a metered-dose aerosol pass into the lungs and almost 80% impact in the oropharynx.
In the case of ethanol-containing solution aerosols, unfortunately there are frequently problems concerning the active compound stability. Active compounds, such as fenoterol and salbutamol are affected by this, which is why such active compounds have preferably been formulated as suspensions until now. To reduce their solubility in the propellant mixture, the polar salts such as fenoterol hydrobromide are also frequently employed.
The invention is therefore based on the object of making available a propellant system with which:
active compounds can be better wetted;
suspension aerosols having improved suspension and shelf-life properties can be prepared;
solution aerosols having improved storage stability and lower addition of ethanol can be prepared;
the dosage accuracy can be improved;
the particle size distribution spectrum and the MMAD can be better adjusted; and/or
the fine particle dose (FPD) can be increased and the oropharyngeal deposition can be reduced.
This object is achieved according to the invention by a pressure-liquefied propellant mixture for aerosols, comprising dinitrogen monoxide and a hydrofluoroalkane of the general formula
CxHyFzxe2x80x83xe2x80x83(I)
in which x is the number 1, 2 or 3, y and z are each an integer xe2x89xa71 and y+z=2x+2.